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Onko (Fach) / x13 Hagenbucher (Lektion)
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- What is the Crabtree effect? In normal cells presence of glucose increases respiration • In cancer cells presence of glucose decreases oxygen uptake – Inhibition of respiration by glucose (Crabtree effect – Herbert Crabtree 1926) • Not only seen in cancer cells but in rapidly dividing cells (thymocytes, spermatozoa, intestinal mucosal cells, and embryonic stem cells) • Cell show high rates of glycolysis which is associated with partial mitochondrial impairment
- What are the advantages for cancer cells to produce ATP via aerobic glycolysis (Warburg effect) instead of oxidative phosphorylation? • Acute and chronic acidification of the local environment – extracellular pH of tumours can reach pH values approaching 6.0 – Normal cell can not survive under these conditions: T-cell inactivation – Additional mutagenic (Inactivation of DNA repair) • Increased invasion and metastasis – Correlation of GLUT1 expression levels and metalloproteinase – Increased degradation of the ECM – Lactate increases hyaluronan (makes cells less adhesive and causes single cells) – Lactate increases CD44, which interacts with the cytoskeleton allowing movements of cells
- How can cancer cells stabilize HIF1α under normoxic conditions? • Mutations in VHL protein: VHL acts as tumor suppressor gene, mutations lead to VHL syndrome • Oncogene Signaling: Ras-MAPK Src PKB/AKT MAPK/ ERK1/2 • TCA Cycle enzymes: enzymes of the TCA cycle stabilize HIF1 • Reactive oxygen species: mitochondrial ROS can also stabilize HIF1
- How does the oncogene MYC contribute to increased glycolysis? Induce expression of glycolytic genes such as hexokinase II, enolase, lactate dehydrogenase, and phosphofructokinase
- How does the loss of p53 increase glycolysis? TIGAR reduces glycolysis by decreasing the expression of fructose-2,6-bisphophate Loss of p53 and therefore TIGAR increases glycolysis.P53 regulates expression of cytochrome oxidase 2 (SCO2) which is necessary for COX complex assembly in the respiratory chain • Loss of p53 and SCO2 shuts down respiration p53 suppresses phosphyglycerate mutase (PGM) which catalyzes the conversion of 3-phosphoglycerate to 2- phosphoglycerate • Loss of p53 enhances PGM and therefore glycolysis
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